Revised_Supplementary_Material_db19-1256.docx (22.59 kB)

Central KATP channels modulate glucose effectiveness in humans and rodents

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posted on 01.05.2020 by Ada Admin, Michelle Carey, Eric Lontchi-Yimagou, William Mitchell, Sarah Reda, Kehao Zhang, Sylvia Kehlenbrink, Sudha Koppaka, Sylvan Roger Maginley, Sandra Aleksic, Shobhit Bhansali, Derek M. Huffman, Meredith Hawkins
Hyperglycemia is a potent regulator of endogenous glucose production (EGP). Loss of this ‘glucose effectiveness’ is a major contributor to elevated plasma glucose concentrations in type 2 diabetes (T2D). ATP-sensitive potassium channels (KATP channels) in the central nervous system (CNS) have been shown to regulate EGP in humans and rodents. We examined the contribution of central KATP channels to glucose effectiveness. Under fixed hormonal conditions (‘pancreatic clamp’ studies), hyperglycemia suppressed EGP by ~50% in both non-diabetic humans and normal Sprague Dawley rats. By contrast, antagonism of KATP channels with glyburide significantly reduced the EGP-lowering effect of hyperglycemia in both humans and rats. Furthermore, the effects of glyburide on EGP and gluconeogenic enzymes in rats were abolished by intracerebroventricular (ICV) administration of the KATP channel agonist diazoxide. These findings indicate that about half of EGP suppression by hyperglycemia is mediated by central KATP channels. These central mechanisms may offer a novel therapeutic target for improving glycemic control in T2D.


This work was supported by the National Institutes of Health (DK048321, DK069861, DK079974), by the Einstein-Montefiore NIH CTSA Grant UL1TR001073 from the National Center for Research Resources (NCRR), the Einstein-Mt. Sinai Diabetes Research Center (5P30DK020541-41) and the Nathan Shock Center (P30AG038072).